Thelma Schilt

Drug-related decrease in neuropsychological functions of abstinent drug users.

This article reviews neuropsychological performance in frequent users of cocaine, (meth)amphetamines, ecstasy, opiates, alcohol, and cannabis. We searched the scientific literature published in the last five years, focusing on studies that required at least 2 weeks of abstinence from drug use, and included a control group. All substances of abuse, except cannabis, were associated with sustained deficits in executive functioning, especially inhibition. In addition, verbal memory decrements were consistently found in cocaine, (meth)amphetamines and ecstasy users, but not in heroin or cannabis users. More specific executive functioning deficits were reported depending on the substance of abuse. Cocaine was associated with diminished cognitive flexibility, whereas (meth)amphetamines were associated with worse cognitive planning functions compared to controls. Opiate studies showed lower scores on verbal fluency in opiate dependent subjects compared to controls. Working memory and visuospatial abilities were compromised in alcohol abusers. In ecstasy users, inconsistent findings have been reported across neuropsychological domains, with the exception of inhibition and verbal memory. There was little evidence for sustained cognitive impairments in adult abstinent cannabis users. Recognition of neuropsychological problems related to different substances can help to select subjects that will benefit most from treatment. Furthermore, a better understanding of the neuropsychological impairments in drug abusing individuals could help to explain the remitting course of substance abuse disorders and to improve psychological interventions.

Sustained effects of ecstasy on the human brain : a prospective neuroimaging study in novel users

Previous studies have suggested toxic effects of recreational ecstasy use on the serotonin system of the brain. However, it cannot be excluded that observed differences between users and non-users are the cause rather than the consequence of ecstasy use. As part of the Netherlands XTC Toxicity (NeXT) study, we prospectively assessed sustained effects of ecstasy use on the brain in novel ecstasy users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. At baseline, 188 ecstasy-naive volunteers with high probability of first ecstasy use were examined. After a mean period of 17 months follow-up, neuroimaging was repeated in 59 incident ecstasy users and 56 matched persistent ecstasy-naives and their outcomes were compared. Neuroimaging included [(123)I]beta-carbomethoxy-3beta-(4-iodophenyl)tropane (CIT) SPECT to measure serotonin transporter densities as indicators of serotonergic function; (1)H-MR spectroscopy ((1)H-MRS) to measure brain metabolites as indicators of neuronal damage; diffusion tensor imaging (DTI) to measure the apparent diffusion coefficient and fractional anisotropy (FA) of the diffusional motion of water molecules in the brain as indicators of axonal integrity; and perfusion weighted imaging (PWI) to measure regional relative cerebral blood volume (rrCBV) which indicates brain perfusion. With this approach, both structural ((1)H-MRS and DTI) and functional ([(123)I]beta-CIT SPECT and PWI) aspects of neurotoxicity were combined. Compared to persistent ecstasy-naives, novel low-dose ecstasy users (mean 6.0, median 2.0 tablets) showed decreased rrCBV in the globus pallidus and putamen; decreased FA in thalamus and frontoparietal white matter; increased FA in globus pallidus; and increased apparent diffusion coefficient in the thalamus. No changes in serotonin transporter densities and brain metabolites were observed. These findings suggest sustained effects of ecstasy on brain microvasculature, white matter maturation and possibly axonal damage due to low dosages of ecstasy. Although we do not know yet whether these effects are reversible or not, we cannot exclude that ecstasy even in low doses is neurotoxic to the brain.

Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users

Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive function. Because 5-HT transporters play a key element in the regulation of synaptic 5-HT transmission it may be important to control for the potential covariance effect of a polymorphism in the 5-HT transporter promoter gene region (5-HTTLPR) when studying the effects of MDMA as well as cognitive functioning. The aim of the study was to investigate the effects of moderate and heavy MDMA use on cognitive function, as well as the effects of longterm abstention from MDMA, in subjects genotyped for 5-HTTLPR. A second aim of the study was to determine whether these effects differ for females and males. Fifteen moderate MDMA users (55 lifetime tablets), 22 heavy MDMA β users (δ 55 lifetime tablets), 16 ex-MDMA β users (last tablet δ 1 year ago) and 13 controls were compared on a battery of neuropsychological tests. DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. A signi.cant group effect was observed only on memory function tasks (p 0.04) but not on reaction times (p 0.61) or attention/ executive functioning (p 0.59). Heavy and ex-MDMA β users performed signi.cantly poorer on memory tasks than controls. In contrast, no evidence of memory impairment was observed in moderate MDMA users. No signi.cant effect of 5-HTTLPR or gender was observed. While the use of MDMA in quantities that may be considered ëmoderateí is not associated with impaired memory functioning, heavy use of MDMA use may lead to long lasting memory impairments. No effect of 5-HTTLPR or gender on memory function or MDMA use was observed.

Assessment of Cognitive Brain Function in Ecstasy Users and Contributions of Other Drugs of Abuse: Results from an fMRI Study

Heavy ecstasy use has been associated with neurocognitive deficits in various behavioral and brain imaging studies. However, this association is not conclusive owing to the unavoidable confounding factor of polysubstance use. The present study, as part of the Netherlands XTC Toxicity study, investigated specific effects of ecstasy on working memory, attention, and associative memory, using functional magnetic resonance imaging (fMRI). A large sample (n=71) was carefully composed based on variation in the amount and type of drugs that were used. The sample included 33 heavy ecstasy users (mean 322 pills lifetime). Neurocognitive brain function in three domains: working memory, attention, and associative memory, was assessed with performance measures and fMRI. Independent effects of the use of ecstasy, amphetamine, cocaine, cannabis, alcohol, tobacco, and of gender and IQ were assessed and separated by means of multiple regression analyses. Use of ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance. Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.

Ecstasy use and self-reported depression, impulsivity, and sensation seeking: a prospective cohort study

Although there are indications that ecstasy users have higher levels of depression, impulsivity, and sensation seeking, it is unknown whether these are consequences of ecstasy use or predisposing factors for starting ecstasy use. We prospectively assessed the predictive value of depression, impulsivity, and sensation seeking on future .rst time ecstasy use. We also assessed whether depression, impulsivity, and sensation seeking had changed after .rst ecstasy use. Depression, impulsivity, and sensation seeking were assessed using self-report questionnaires in 188 ecstasynaive volunteers with high probability for future ecstasy use. After a mean follow-up of 17 months, measurements were repeated in 59 incident ecstasy users (mean 6.0 tablets) and 61 matched persistent ecstasy-naive volunteers. Only experience seeking (subscale of the sensation seeking scale) predicted future ecstasy use (OR -- 1.05, 95% CI 1.00 to 1.10), but after adjustment for potential confounders this was not signi.cant anymore. At follow-up, signi.cant effects of ecstasy use on the general and the disinhibition subscale of the sensation seeking scale were observed (after adjustment for potential confounders: regression coef.cient B 0.51, 95% CI 0.20 to 0.83 and B -- 3.25, 95% CI 1.74 to 4.76, respectively). These data indicate that depression, impulsivity, and sensation seeking do not predict .rst time ecstasy use in a population of young adults with the intention to start using ecstasy and that low level ecstasy use does not seem to cause depression or impulsivity. However, low level ecstasy use may increase (certain aspects of) sensation seeking.

Recovery of neurocognitive functions following sustained abstinence after substance dependence and implications for treatment

BACKGROUND Substance Use Disorders (SUDs) have been associated with impaired neurocognitive functioning, which may (partly) improve with sustained abstinence. New treatments are emerging, aimed at improving cognitive functions, and being tested. However, no integrated review is available regarding neurocognitive recovery following sustained abstinence. OBJECTIVES In this review, results from prospective studies on neurocognitive recovery using neuropsychological assessments before and after sustained abstinence from SUDs are summarized and discussed. RESULTS Thirty-five prospective studies were selected for this review, including twenty-two alcohol, three cannabis, four cocaine, three (meth)amphetamine, and three opioid studies. Results suggest that some cognitive functions (partially) recover after sustained abstinence, and that there are predictors of an unfavorable course such as poly-substance use and number of previous detoxifications. CONCLUSIONS Prospective studies indicate that sustained abstinence after SUDs generally results in (partial) neurocognitive recovery. However, a final answer regarding full recovery awaits prospective studies with neurocognitive assessments before, during, and after sustained abstinence from SUDs. New interventions that might enhance neurocognitive recovery after abstinence are discussed, including neurocognitive training, medication and neuromodulation.

Neurotoxic effects of ecstasy on the thalamus.

BACKGROUND Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. AIMS To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study. METHOD Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses. RESULTS Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients. CONCLUSIONS Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

The effect of Ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene.

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose-response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional val (158)met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous val-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

Long-term neuropsychological effects of ecstasy in middle-aged ecstasy/polydrug users

RationaleStudies reporting ecstasy-induced serotonin-toxicity and (neuro)psychological dysfunctions have been conducted in young adults. Little is known about ecstasy effects later in life, when serotonin levels and cognition decrease as a consequence of normal ageing.ObjectiveThis study aimed to assess whether harmful effects of ecstasy only add to or also interact with age-related neuropsychological decline.MethodsAttention, verbal and visual memory, visuospatial ability, self-reported depression, sensation-seeking and impulsivity were assessed in middle-aged moderate to heavy ecstasy/polydrug users (n = 17) and compared with none or very mild ecstasy using polydrug users (matched for age, gender, intelligence and other drugs; n = 16) and a group of drug-naive controls (n = 20).ResultsModerate to heavy ecstasy/polydrug users performed significantly worse on a verbal memory task than none or very mild ecstasy using polydrug users and drug naives. Moderate and heavy ecstasy/polydrug users also differed significantly from drug-naives on measures of depression, sensation-seeking and impulsivity but not from none or very mild ecstasy-using polydrug users.ConclusionThis study in middle-aged ecstasy/polydrug users replicated findings of studies in younger ecstasy users, showing a harmful effect of ecstasy on verbal memory. There was no clear support for an interaction between harmful effects of ecstasy use and age-related memory decline or mid-life depression.

One Size Does Not Fit All: Comparative Diagnostic Accuracy of the Rowland Universal Dementia Assessment Scale and the Mini Mental State Examination in a Memory Clinic Population with Very Low Education

Background: Diagnosing dementia in elderly immigrants is often difficult due to language and cultural barriers, low education, and illiteracy. We compared the diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) to that of the Mini Mental State Examination (MMSE). Methods: A total of 144 patients (42 with intact cognition, 44 with mild cognitive impairment [MCI], and 58 with dementia) were administered both instruments and were diagnosed by specialists blinded for MMSE and RUDAS results. Results: Areas under the curve for discriminating intact cognition from MCI and dementia were comparable for RUDAS (0.81; 95% confidence interval 0.74–0.88) and MMSE (0.75; 95% confidence interval 0.69–0.85). Education and literacy were not correlated with the RUDAS but had a medium-large correlation with the MMSE (rho = 0.39). Conclusions: The study provides additional evidence for the usefulness of the RUDAS in a highly illiterate, culturally diverse geriatric outpatient population.